The present invention relates to pyrazinoindole derivatives, to pharmaceutical compositions containing them and to their medicinal use. The active compounds of the present invention are useful in treating obesity and other disorders.
It has been recognised that obesity is a disease process influenced by environmental factors in which the traditional weight loss methods of dieting and exercise need to be supplemented by therapeutic products (S. Parker, xe2x80x9cObesity: Trends and Treatmentsxe2x80x9d, Scrip Reports, PJB Publications Ltd, 1996).
Whether someone is classified as overweight or obese is generally determined on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m2). Thus, the units of BMI are kg/m2 and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. Overweight is defined as a BMI in the range 25-30 kg/m2, and obesity as a BMI greater than 30 kg/m2. There are problems with this definition in that it does not take into account the proportion of body mass that is muscle in relation to fat (adipose tissue). To account for this, obesity can also be defined on the basis of body fat content: greater than 25% and 30% in males and females, respectively.
As the BMI increases there is an increased risk of death from a variety of causes that is independent of other risk factors. The most common diseases with obesity are cardiovascular disease particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and diseases of reproduction. Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.
Compounds marketed as anti-obesity agents include Orlistat (Reductil(copyright)) and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorption directly and tends to produce a high incidence of unpleasant (though relatively harmless) side-effects such as diarrhoea. Sibutramine (a mixed 5-HT/noradrenaline reuptake inhibitor) can increase blood pressure and heart rate in some patients. The serotonin release/reuptake inhibitors fenfluramine (Pondimin(copyright)) and dexfenfluramine (Redux(trademark)) have been reported to decrease food intake and body weight over a prolonged period (greater than 6 months). However, both products were withdrawn after reports of preliminary evidence of heart valve abnormalities associated with their use. There is therefore a need for the development of a safer anti-obesity agent.
The non-selective 5-HT2C receptor agonists/partial agonists m-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine (TFMPP) have been shown to reduce food intake in rats (G. A. Kennett and G. Curzon, Psychopharmacol., 1988, 98, 93-100, G. A. Kennett, C. T. Dourish and G. Curzon, Eur. J. Pharmacol., 1987, 141, 429-453) and to accelerate the appearance of the behavioural satiety sequence (S. J. Kitchener and C. T. Dourish, Psychopharmacol., 1994, 113, 369-377). Recent findings from studies with mCPP in normal human volunteers and obese subjects have also shown decreases in food intake. Thus, a single injection of mCPP decreased food intake in female volunteers (A. E. S. Walsh et al., Psychopharmacol., 1994, 116, 120-122) and decreased the appetite and body weight of obese male and female subject during subchronic treatment for a 14 day period (P. A. Sargeant et al., Psychopharmacol., 1997, 113, 309-312). The anorectic action of mCPP is absent in 5-HT2C receptor knockout mutant mice (L. H. Tecott et al., Nature, 1995, 374, 542-546) and is antagonised by the 5-HT2C receptor antagonist SB-242084 in rats (G. A. Kennett et al., Neuropharmacol., 1997, 36, 609-620). It seems therefore that mCPP decreases food intake via an agonist action at the 5-HT2C receptor. However, although both mCPP and TFMPP exhibit high affinity for the 5-HT2C receptor they are both non-selective, having appreciable activity at other 5-HT receptors (G. A. Kennett, Curr. Opin. Invest. Drugs, 1993, 2, 317-362).
The preparation of pyrazino[1,2-a]indoles as serotonergic agents, useful as antidepressants and anxiolytics, is disclosed in PCT application WO 9612721. The compounds of this invention are reported to possess high affinity for the serotonergic 5-HT1A receptor. Substituted pyrazino[1,2-a]indoles are used as intermediates in the preparation of heterocyclyl O-substituted alcoholamines as fibrinogen receptor antagonist products as disclosed in PCT application WO 9800401. Pyrazino[1,2-a]indole derivatives are also reported in the preparation of 3-piperazinomethylpyrrolo[2,3-b]pyridines as dopamine D4 receptor antagonists as disclosed in U.S. Pat. No. 5,576,319 and WO 9420497. 1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indole and 3-ethyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole are disclosed in Med. Chem. Res., 1993, 3, 240-248 and their 5-HT1A and 5-HT2 binding affinity reported. The 5-HT1A and 5-HT2 binding affinity for 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole is reported to be the same as that observed for 1-phenylpiperazine and demonstrates an approximate ten fold selectivity for 5-HT1A receptors.
It is an object of this invention to provide selective, directly acting 5-HT2 receptor ligands for use in therapy and particularly for use as anti-obesity agents. It is a further object of this invention to provide directly acting ligands selective for 5-HT2B and/or 5-HT2C receptors, for use in therapy and particularly for use as anti-obesity agents. It is a further object of this invention to provide selective, directly acting 5-HT2C receptor ligands, preferably 5-HT2C receptor agonists, for use in therapy and particularly for use as anti-obesity agents.
According to the present invention there is provided a chemical compound of formula (I): 
wherein:
R1 to R3 are independently selected from hydrogen and lower alkyl;
X1 is selected from N and Cxe2x80x94R4;
X2 is selected from N and Cxe2x80x94R5;
X3 is selected from N and Cxe2x80x94R6;
X4 is selected from N and Cxe2x80x94R7;
R4, R5 and R7 are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, alkoxy, aryloxy, alkoyl aryloyl, alkylthio, arylthio, alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl, amino, alkylamino, dialkylamino, nitro, cyano, carboalkoxy, carboaryloxy and carboxy; and
R6 is selected from hydrogen, halogen, alkyl, aryl, aryloxy, alkylthio, arylthio, alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl, amino, alkylamino, dialkylamino and cyano;
with the proviso that R4 to R7 are not all selected as hydrogen, and pharmaceutically acceptable salts and addition compounds and prodrugs thereof.
As used herein, the term xe2x80x9calkylxe2x80x9d means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical which may be substituted or unsubstituted. Where cyclic, the alkyl group is preferably C3 to C12, more preferably C5 to C10, more preferably C5 to C7. Where acyclic, the alkyl group is preferably C1 to C10, more preferably C1 to C6, more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl and isopentyl), more preferably methyl. It will be appreciated therefore that the term xe2x80x9calkylxe2x80x9d as used herein includes alkyl (branched or unbranched), substituted alkyl (branched or unbranched), alkenyl (branched or unbranched), substituted alkenyl (branched or unbranched), alkynyl (branched or unbranched), substituted alkynyl (branched or unbranched), cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloalkynyl and substituted cycloalkynyl.
As used herein, the term xe2x80x9clower alkylxe2x80x9d means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical wherein said cyclic lower alkyl group is C5, C6 or C7, and wherein said acyclic lower alkyl group is C1, C2, C3 or C4, and is preferably selected from methyl, ethyl propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl). It will be appreciated therefore that the term xe2x80x9clower alkylxe2x80x9d as used herein includes lower alkyl (branched or unbranched), lower alkenyl (branched or unbranched), lower alkynyl (branched or unbranched), cycloloweralkyl, cycloloweralkenyl and cycloloweralkynyl.
As used herein the term xe2x80x9carylxe2x80x9d means a substituted or unsubstituted carbocyclic aromatic group, such as phenyl or naphthyl, or a substituted or unsubstituted heteroaromatic group containing one or more, preferably one, heteroatom, such as pyridyl, pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl pyrazolyl, imidazolyl, triazolyl, pyrimidinyl pyridazinyl, pyrazinyl, triazinyl, indolyl, indazolyl, quinolyl, quinazolyl, benzimidazolyl, benzothiazolyl, benzixazolyl and benzisothiazolyl.
The alkyl and aryl groups may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include:
carbon-containing groups such as
alkyl,
aryl,
arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl);
halogen atoms and halogen-containing groups such as
haloalkyl (e.g. trifluoromethyl);
oxygen-containing groups such as
alcohols (e.g. hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl),
ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl),
aldehydes (e.g. carboxaldehyde),
ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl),
acids (e.g. carboxy, carboxyalkyl),
acid derivatives such as esters (e.g. alkoxycarbonyl alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl),
amides (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl, aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl, arylaminocakbonyl),
carbamates (e.g. alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, arylaminocarbonyloxy)
and ureas (e.g. mono- or di-alkylaminocarbonylamino or arylaminocarbonylamino);
nitrogen-containing groups such as
amines (e.g. amino, mono- or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl),
azides,
nitriles (e.g. cyano, cyanoalkyl),
nitro;
sulfur-containing groups such as
thiols, thioethers, sulfoxides and sulfones
(e.g. alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl);
and heterocyclic groups containing one or more, preferably one, heteroatom,
(e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl and carbolinyl).
The lower alkyl groups may be substituted or unsubstituted, preferably unsubstituted. Where substituted there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents include the substituent groups listed above other than alkyl aryl and arylalkyl.
As used herein, the term xe2x80x9calkoxyxe2x80x9d means alkyl-Oxe2x80x94 and xe2x80x9calkoylxe2x80x9d means alkyl-COxe2x80x94. Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by one or more alkyl groups.
As used herein, the term xe2x80x9chalogenxe2x80x9d means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine chlorine or bromine radical, and more preferably a fluorine or chlorine radical.
As used herein the term xe2x80x9cprodrugxe2x80x9d means any pharmaceutically acceptable prodrug of the compound of formula (I) which is metabolised in vivo to a compound of formula (I).
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d means any pharmaceutically acceptable salt of the compound of formula (I). Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are fumaric, hydrochloric, hydrobromic, phosphoric, succinic, succinic, sulfuric and methanesulfonic acid. Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
Preferably, R1 is hydrogen or C1-C4 acyclic lower alkyl, preferably hydrogen or saturated C1-C4 acyclic lower alkyl, preferably hydrogen or methyl. In one embodiment of the invention, R1 is hydrogen.
Preferably, R2 is hydrogen or C1-C4 acyclic lower alkyl, preferably hydrogen or saturated C1-C4 acyclic lower alkyl, preferably hydrogen or methyl, more preferably hydrogen.
Preferably, R3 is hydrogen or C1-C4 acyclic lower alkyl, preferably hydrogen or saturated C1-C4 acyclic lower alkyl preferably hydrogen or methyl. In one embodiment of the invention, R3 is hydrogen.
In one embodiment of the invention, R1 and R3 are indepently selected from hydrogen and lower alkyl preferably hydrogen and methyl, and R2 is hydrogen. In a further embodiment, R1,R2 and R3 are hydrogen.
Preferably, X1 is Cxe2x80x94R4.
Preferably, X2 is Cxe2x80x94R5.
Preferably, X3 is Cxe2x80x94R6.
Preferably, X4 is Cxe2x80x94R7.
In one embodiment, only one of X1 to X4 is nitrogen. In this embodiment, preferably X1 is N, X2 is Cxe2x80x94R5, X3 is Cxe2x80x94R6 and X4 is C-R7.
R4, R5 and R7 are independently selected from hydrogen, halogen, hydroxy, alkyl (including cycloalkyl halo-alkyl (such as trifluoromethyl) and arylalkyl), aryl alkoxy (including arylalkoxy), aryloxy, alkoyl, aryloyl, alkylthio, arylthio, alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl, amino, alkylamino, dialkylamino, nitro, cyano, carboalkoxy, carboryloxy and carboxy.
Preferably, R4 is selected from hydrogen and halogen. Preferably, R4 is hydrogen.
Preferably R5 is selected from hydrogen, halogen, alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl) and arylalkyl), aryl, aryloxy, alkylthio, arylthio, alkylsulfoxyl, arylsulfoxyl alkylsulfonyl arylsulfonyl, amino, alkylamino, dialkylamino and cyano. In one embodiment, R5 is selected from halogen, halo alkyl (such as trifluoromethyl) and alkylthio, preferably from halogen and alkylthio, and preferably from halogen.
R6 is selected from hydrogen, halogen, alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl) and arylalkyl), aryl, aryloxy, alkylthio, arylthio, alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl, amino, alkylamino, dialkylamino and cyano. In one embodiment, R6 is selected from hydrogen, lower alkyl and halogen, preferably from hydrogen and loweralkyl, and more preferably from hydrogen.
Preferably, R7 is selected from hydrogen and halogen, preferably from halogen.
In one embodiment, R5 and R6 are independently selected from hydrogen, chlorine, fluorine, haloalkyl (such as trifluoromethyl) and bromine. In this embodiment, preferably, at least one of R5 and R6, preferably R5, is selected from chlorine, fluorine, haloalkyl (such as trifluoromethyl) and bromine.
In one embodiment of the invention, three of R4 to R7 are hydrogen. In this embodiment, preferably at least R4 and R6 are hydrogen, and more preferably R4, R6 and R7 are hydrogen.
In the embodiment where R4, R6 and R7 are hydrogen and R5 is a substituent group other than hydrogen the preferred stereochemistry at the 10a position is R and, where R3 is alkyl, the preferred stereochemistry at the 3 position is S.
In a further embodiment of the invention, two of R4 to R7 are hydrogen. In this embodiment, preferably at least R4 is hydrogen, more preferably R4 and R5 or R4 and R7 or R4 and R6 are hydrogen, and most preferably R4 and R6 are hydrogen.
In a preferred embodiment, the compounds of the present invention are selected from (RS) 7-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole, (RS) 9-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole, (RS) 7-chloro-8-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole, (10aR) 7-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole, (RS) 7-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole and (3S, 10aR) 8-chloro-2-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole, and particularly from (10aR) 8-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole and (3S, 10aR) 8-chloro-2-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole. In one embodiment, the compounds are in the form of the hydrochloride salt.
The compounds of the invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. The compounds can be, for example, racemates or optically active forms. The optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis.
According to a further aspect of the invention, there is provided a compound of formula (I) for use in therapy.
The compounds of formula (I) may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT2 receptor function The compounds may act as receptor agonists or antagonists. Preferably, the compounds may be used in the treatment (including prophylactic treatment) of disorders associated with 5-HT2B and/or 5-HT2C receptor function. Preferably, the compounds may be used in the treatment (including prophylactic treatment) of disorders where a 5HT2C receptor agonist is required.
The compounds of formula (I) may be used in the treatment or prevention of central nervous disorders such as depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioural disorders, behavioural disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, anorexia nervosa or premenstrual tension; damage of the central nervous system such as by trauma, stroke, neurodegenerative diseases or toxic or infective CNS diseases such as encephalitis or meningitis; cardiovascular disorders such as thrombosis; gastrointestinal disorders such as dysfunction of gastrointestinal motility; diabetes insipidus; and sleep apnea.
According to a further aspect of the invention, there is provided use of a compound of formula (I) in the manufacture of a medicament for the treatment (including prophylaxis) of the above-mentioned disorders. In a preferred embodiment, there is provided use of a compound of formula (I) in the manufacture of a medicament for the treatment (including prophylaxis) of obesity.
According to a further aspect of the invention, there is provided a method of treating a disorder selected from the group consisting of the above-mentioned disorders comprising administering to a patient in need of such treatment an effective dose of a compound of formula (I). In a preferred embodiment, there is provided a method of treatment (including prophylaxis) of obesity.
According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of formula (I) with a pharmaceutically acceptable carrier or excipient.
According to a further aspect of the invention, there is provided a method of preparing a compound of formula (I).
Compounds of the invention may be prepared by conventional methods as illustrated in the Reaction Schemes. R1 to R7 and X1 to X4 are as previously defined. 
Compounds of formula (I), with X1 to X4 as previously defined and R1=R=R3=H are conveniently prepared as indicated in Reaction Scheme 1. The methyl 1-(cyanomethyl)indole-2-carboxylate (III) can be obtained through reaction of the sodium salt of indole carboxylate (II), prepared through treatment of (II) with a base such as sodium hydride in a solvent such as dimethylformamide with a cyanomethylation agent such as chloroacetonitrile. Reduction of (III) to the tetrahydropyrazino[1,2-a]indole (IV) may be achieved with a reducing agent such as lithium aluminium hydride in a suitable solvent such as ether. A compound of formula (I) can the be obtained by the subsequent reduction of the tetrahydropyrazinol[1,2-a]lindole (IV) with a reducing agent such as sodium cyanoborohydride in a suitable solvent such as acetic acid.
Compounds of formula (I), with X1 to X4 as previously defined and R1=R3=H and R2=loweralkyl are conveniently prepared by standard methods such as reductive alkylation with an appropriate aldehyde or ketone in the presence of a reducing agent such as sodiumtriacetoxyborohydride, formic acid or sodium cyanoborohydride. 
Compounds of formula (I), with X1 to X4 as previously defined and R1=R2H and R3=Methyl are conveniently prepared as indicated in Reaction Scheme 2. The dihydroindole carboxylate (V) can be obtained from the indole carboxylate (II) through reduction with a reducing agent such as magnesium in methanol. The dihydro indole alanine ester derivative (VI) can be prepared by treatment of the dihydroindole (V) with a suitably protected alanine derivative such as BOC-alanine in the presence of a coupling agent such as dicyclohexylcarbodiimide (DCC) in a suitable solvent such as dichloromethane. The pyrazino[1,2-a]indole-1,4-dione derivative (VII) can subsequently be prepared by sequential treatment of (VI) with an acid such as hydrogen chloride in methanol followed by a base such as ammonia in methanol. Compounds of formula (I) can then be obtained by reduction of (VII) with a suitable reducing agent such as lithium aluminium hydride in a solvent such as tetrahydrofuran.
Compounds of formula (I), with X1 to X4 as previously defined and R1=R3=H and R2=lower alkyl are conveniently prepared by standard methods such as reductive alkylation with an appropriate aldehyde or ketone in the present of a reducing agent such as sodium triacetoxyborohydride, formic acid or sodium cyanoborohydride. 
Compounds of formula (I), with X1 to X4 as previously defined are conveniently prepared according to Reaction Scheme 3 (above). The indole-ethylamine (IX) can be obtained by alkylation of the indole (VIII) using, for example, chloroethylamine and a base such as sodium hydroxide in a solvent such as acetonitrile or dichloromethane in the presence of a phase-transfer catalyst The tetrahydropyrazino[1,2-a]indole (X) can be prepared in a two-step procedure from the indole-ethylamine (IX) by treatment with an aldehyde such as formaldehyde followed by exposure to an acid such as trifluoroacetic acid. A compound of formula (I) can then be obtained by reduction of the tetrahydropyrazino[1,2-a]indole (X) using a reducing agent such as sodium cyanoborohydride in a solvent such as acetic acid.
Compounds of formula (I) where R2=loweralkyl may conveniently be prepared from compounds of formula (I) where R2=H using standard methods such as reductive alkylation with an aldehyde or ketone in the presence of a reducing agent such as sodium triacetoxyborohydride, formic acid or sodium cyanoborohydride.
If, in any of the other processes mentioned herein, the substituent group R4, R5, R6 or R7 is other than the one required, the substituent group may be converted to the desired substituent by known methods. The substituents R4, R5, R6 or R7 may also need protecting against the conditions under which the reaction is carried out. In such a case, the protecting group may be removed after the reaction has been completed.
The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from basic compounds.
According to a further aspect of the invention, there is provided a process for the preparation of a compound of formula (I) comprising the steps of
(i) treating a compound of formula (IX) as described herein with an aldehyde and then exposing to acid to obtain a compound of formula (X) as described herein, and
(ii) reduction of a compound of formula (X).
The reagents used to effect steps (i) to (ii) may be those described with reference to the corresponding steps in Reaction Scheme 3 herein. In a preferred embodiment of this aspect of the invention, the compound of formula (IX) is an indole-ethylamine and the compound of formula (X) is a tetrahydropyrazino[1,2-a]indole.
According to a further aspect of the invention there is provided a process for the production of a compound of formula (X) as described herein comprising the steps of treating a compound of formula (IX) as described herein with an aldehyde and then exposing to acid. The aldehyde may be formaldehyde. The acid may be trifluoroacetic acid. In a preferred embodiment, the compound of formula (IX) is an indole-ethylamine and the compound of formula (X) is a tetrahydropyrazino[1,2-a]indole.
The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) transdermal or rectal administration or in a form suitable for administration by inhalation or insulation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
A suitable dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., obesity) is 0.1 to 500 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
The invention will now be described in detail with reference to the following examples. It will be appreciated that the invention is described by way of example only and modification of detail may be made without departing from the scope of the invention.